More than 30% of patients with epilepsy have inadequate control of seizures despite the choice of an adequate antiepileptic drug (AED) and carefully monitored treatment. Pharmacoresistant epilepsy is a major health problem, associated with increased morbidity and mortality, and accounting for much of the economic burden of epilepsy. A striking obstacle in developing new strategies for treatment of pharmacoresistant epilepsy is that mechanisms of pharmacoresistance are only poorly understood. Despite the problem of intractable epilepsy, there are only few models specifically dedicated to identify effective therapeutic agents for resistant epilepsy or to study mechanisms of drug resistance. Thus, new methods for evaluating the therapeutic potential of novel compounds for the treatment of refractory epilepsy are urgently needed. An animal model of epilepsy allowing selection of pharmacoresistant and pharmacosensitive subgroups of animals would be particularly valuable to study mechanisms of intractability and to develop more efficacious treatment strategies.
The specific aim of this proposal is to study whether AED non-responders and responders can be selected by prolonged drug treatment from rat models of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures. Two models in which spontaneous recurrent seizures develop after either chemical or electrical induction of a status epilepticus will be examined in this respect. In each model, two to three AED will be daily administered at anticonvulsant doses for two weeks and drug plasma levels are controlled over this period. For comparison with the treatment period, each rat is recorded two weeks before and after the drug treatment, resulting in a length of each drug trial of six weeks. Rats with persistent seizure activity not responding or with very poor response to at least two AED at maximum tolerated doses are considered pharmacoresistant. Our goal is to establish standard assays that can be employed by researchers to continue the search for treatments of drug resistant epilepsy. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS049592-01
Application #
6829366
Study Section
Special Emphasis Panel (ZNS1-SRB-W (07))
Program Officer
Stables, Jim
Project Start
2004-09-21
Project End
2006-07-31
Budget Start
2004-09-21
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$99,900
Indirect Cost
Name
Hanover School of Veterinary Medicine
Department
Type
DUNS #
City
Hannover
State
Country
Germany
Zip Code
Barker-Haliski, Melissa; Harte-Hargrove, Lauren C; Ravizza, Teresa et al. (2018) A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force. Epilepsia Open 3:53-68
Löscher, Wolfgang (2016) Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res 126:157-84
Brandt, Claudia; Löscher, Wolfgang (2014) Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: a pilot study. Epilepsy Res 108:1145-57
Loscher, Wolfgang (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20:359-68
Loscher, Wolfgang; Brandt, Claudia (2010) Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 62:668-700
Löscher, Wolfgang; Langer, Oliver (2010) Imaging of P-glycoprotein function and expression to elucidate mechanisms of pharmacoresistance in epilepsy. Curr Top Med Chem 10:1785-91
Loscher, Wolfgang; Brandt, Claudia (2010) High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia 51:89-97
Loscher, Wolfgang (2009) Molecular mechanisms of drug resistance in status epilepticus. Epilepsia 50 Suppl 12:19-21
Gastens, Alexandra M; Brandt, Claudia; Bankstahl, Jens P et al. (2008) Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia 49:1759-76
Bethmann, Kerstin; Fritschy, Jean-Marc; Brandt, Claudia et al. (2008) Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis 31:169-87

Showing the most recent 10 out of 18 publications